A drug-repositioning screen for primary pancreatic ductal adenocarcinoma cells identifies 6-thioguanine as an effective therapeutic agent for TPMT-low cancer cells.

Abstract

Pancreatic cancer is one of the most difficult cancers to cure due to the lack of early diagnostic tools and effective therapeutic agents. In this study, we aimed to isolate new bioactive compounds that effectively kill pancreatic ductal adenocarcinoma (PDAC) cells, but not untransformed, human pancreatic ductal epithelial (HPDE) cells. To this end, we established four primary PDAC cell lines and screened 4141 compounds from four bioactive-compound libraries. Initial screening yielded 113 primary hit compounds that caused over a 50% viability reduction in all tested PDAC cells. Subsequent triplicate, dose-dependent analysis revealed three compounds with a tumor cell-specific cytotoxic effect. We found that these three compounds fall into a single category of thiopurine biogenesis. Among them, 6-thioguanine (6-TG) showed an IC50 of 0.39-1.13 μm toward PDAC cells but had no effect on HPDE cells. We propose that this cancer selectivity is due to differences in thiopurine methyltransferase (TPMT) expression between normal and cancer cells. This enzyme is responsible for methylation of thiopurine, which reduces its cytotoxicity. We found that TPMT levels were lower in all four PDAC cell lines than in HPDE or Panc1 cells, and that knockdown of TPMT in HPDE or Panc1 cells sensitized them to 6-TG. Lastly, we used a patient-derived xenograft model to confirm that 6-TG has a significant antitumor effect in combination with gemcitabine. Overall, our study presents 6-TG as a strong candidate for use as a therapeutic agent against PDAC with low levels of TPMT.

• Authors: Inki Kim, Yeon-Sook Choi, Jae Hwi Song, Eun A Choi, Sojung Park, Eun Ji Lee, Je-Keun Rhee, Song Cheol Kim, Suhwan Chang
• Journal: Molecular oncology (Mol Oncol) Vol. 12 Issue 9 Pg. 1526-1539 (09 2018) ISSN: 1878-0261 [Electronic] United States
• PMID: 30055072 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.

Chemical References

• Antimetabolites, Antineoplastic
• Deoxycytidine
• Methyltransferases
• TPMT protein, human
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Thioguanine
• Gemcitabine

Topics

• Antimetabolites, Antineoplastic (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols
• Apoptosis (drug effects)
• Carcinoma, Pancreatic Ductal (drug therapy, enzymology)
• Cell Line, Tumor
• Deoxycytidine (analogs & derivatives, therapeutic use)
• Drug Evaluation, Preclinical
• Humans
• MAP Kinase Signaling System (drug effects)
• Methyltransferases (biosynthesis)
• Pancreatic Neoplasms (drug therapy, enzymology)
• Proto-Oncogene Proteins B-raf (metabolism)
• Signal Transduction (drug effects)
• Thioguanine (therapeutic use)
• Treatment Outcome
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays
• Gemcitabine